Prevention Of Venous Thromboembolism In The Cancer Surgical Patient

1
Prevention Of Venous Thromboembolism In The
Cancer Surgical Patient

• A K Kakkar
• Barts and the London School of Medicine
  andThrombosis Research Institute, London UK

2
Incidence Of VTE In Cancer Surgical Patients
Surgical procedure VTE no malignancy () VTE malignancy ()
Neurosurgery 0.52.3 2.03.6
Head and neck 0.10.2 0.21.4
Gastrointestinal 0.21.6 0.92.6
Urological 0.31.0 0.43.7
Gynaecological 0.3 1.22.3
Orthopaedic 0.22.4 0.93.1
Symptomatic VTE at 91 days in patients after
surgery.
Adapted from White et al. Thromb Haemost.
200390446-55.
3
Impact Of Cancer On PE Frequency
Cancer No Cancer OR
Surgical () 2.34 0.36 6.7
Non surgical () 0.73 0.10 7.3
Total 1.84 0.27 6.8

Adapted from Huber et al. Arch Surg
1992127310-3.
4
Prognostic Risk Factors For VTE In Cancer
Variable Effect No. of patients VTE / non-VTE OR 95 CI
Age 60 vs lt 60 years 60 yrs 42 / 1,516 lt 60 yrs 8 / 807 2.6 1.25.7
Previous VTE Yes vs no Yes 5 / 36 No 45 / 2,287 6.0 2.116.8
Anaesthesia 2 vs lt 2 hours 2 hours 48 / 1,762 lt 2 hours 2 / 561 4.5 1.119.0
Stage Advanced vs not advanced Advanced 38 / 1,078 Non advanced 12 / 1,245 2.7 1.45.2
Bedrest 4 vs lt 4 days 4 days 25 / 346 lt 4 days 25 / 1,977 4.4 2.57.8
Adapted from Agnelli et al. Ann Surg 2006
24389-95.
5
Prophylaxis Against Fatal PE With Low-dose UFH

• International Multicenter Trial
• 4121 patients undergoing major surgery
• Primary end point fatal PE
• Randomized control or UFH (5000 IU 2 hours
  before surgery and every 8 hours
  postoperativelyfor 7 days)
• 180 patients died during the postoperative
  period 100 in the control group and 80 in the
  UFH group
• Rate of autopsy was 72 in control group and 66
  in the heparin group

Adapted from Kakkar et al. Lancet 1975245-51.
6
Prophylaxis Against Fatal PE With Low-dose UFH
Plt0.005
18
16
16
14
12
Number of patientswith fatal PE
10
8
6
4
2
2
0
Control
UFH
Adapted from Kakkar et al., Lancet 1975245-51.
7
Fatal Post-operative PE In Patients With Cancer

• 23 (n 953) underwent operation with malignant
  disease

Patients with PE,
Adapted from Kakkar et al. Lancet 1975245-51.
8
Heparin Prevents Death After Surgery

• 21 reduction in total surgical mortality
• 68 reduction in fatal PE
• 67 reduction in asymptomatic DVT

Reduction in fatal pulmonary embolism and venous
thrombosis by perioperative administration of
subcutaneous heparin
Adapted from Collins et al. New Engl J Med
19883181162-73.
9
Death From PE But Not From Bleeding
Other deaths
PE

1. (3.0)

(1.7) 109
Fatal bleeds
(0.9)
(0.3)
7
6
Adapted from Collins et al. N Engl J Med
19883181162-73.
10
Low Dose vs. LMW Heparin
Canadian Colorectal DVT Prophylaxis Trial
16.9
P0.05
N234
13.9
N241
Incidence of Outcome Event
1.5 2.7
N653
N643
VTE Major Bleeding (Cancer)
(All)
Adapted from McLeod et al. Ann Surg
2001233438-44.
11
Thromboprophylaxis In Cancer Surgery
P0.001

• Prospective, randomized, double-blind multicenter
  trial
• LMWH once daily
• Dalteparin 2500 IU vs 5000 IU daily
• Total duration 7 days
• Therapy commenced preoperatively
• 2070 patients randomized
• 67 (1303/1957) malignancy

DVT in Patients With Malignancy ()
Bleeding complications in patients operated on
for malignant disease occurred in 3.6 of those
receiving dalteparin 2500 IU and 4.6 of those
receiving dalteparin 5000 IU (PNS).
Adapted from Bergqvist et al. Br J Surg.
199582496-501.
12
Thromboprophylaxis In The Cancer Surgical Patient
LMWH better UFH better
Asymptomatic DVT
Clinical PE
Clinical thromboembolism
Cancer
Death
Non-cancer
Major hemorrhage
Total hemorrhage
Wound hematoma
Transfusion
0 1.0 2.0 3.0 4.0
Adapted from Mismetti et al. Br J Surg
20018891330.
13
Effects Of Compression Methods of
Thromboprophylaxis On DVT
No. of Deep venous Stratified Odds ratio and
odds trials thrombosis statistics confidence
interval reduction Category with data
Compression Control OE Variance (compression
control) (SE)

• Compression (monotherapy)Graduated 9 57/665 133/6
  27 39.7 37.2 66 (10) compression
  stockings (8.6) (21.2)Intermittent 19 112/1108
  268/1147 76.3 71.0 66 (7) pneumatic
  compression (10.1) (23.4)Footpump 2 11/61 34/6
  5 10.7 7.3 77 (19) (18.0) (52.3)
• 30 180/1834 435/1839 126.7 115.5 67
  (6) (9.8) (23.7) 2p lt 0.00001

99 or 95 confidence intervals 0.0 0.5 1.0 1.5 2
.0 Compression Compression better wo
rse
Treatment effect 2p lt 0.00001
Adapted from Roderick et al. Health Technology
Assessment 2005 Vol. 9 No. 49.
14
Effects Of Compression Methods of
Thromboprophylaxis On PE
No. of Deep venous Stratified Odds ratio and
odds trials thrombosis statistics confidence
interval reduction Category with data
Compression Control OE Variance (compression
control) (SE)

• (a) Compression (monotherapy)Graduated 3 0/123 4/
  90 1.8 0.9 compression stockings (0.0) (4.4)
  Intermittent 8 14/590 18/618 1.6 7.6 pneumatic
  compression (2.4) (2.9)Footpump 1 0/28 0/32
  (0.0) (0.0) 12 14/741 22/740 3.4 8.5 33
  (28) (1.9) (3.0) 2p gt 0.1 NS

99 or 95 confidence intervals 0.0 0.5 1.0 1.5 2
.0 Compression Compression better wo
rse
Treatment effect 2p 0.006
Adapted from Roderick et al. Health Technology
Assessment 2005 Vol. 9 No. 49.
15
Combined Mechanical and Pharmacological
Prophylaxis
Intervention
LDH (n451)
LDHGCS (n439)
RR (95CI)
6 studies
83 (18)
35 ()
0.47 0.33-0.69
DVT n ()
Adapted from IUA Consensus statement Int Angiol
2006.
16
Prevention Of Fatal PE In Surgical Patients
PNS
Low-dose heparin t.i.d.
LMWH o.d.
Adapted from Haas et al. Thromb Haem.
200594814-9.
17
Cancer Patients Are At Higher Risk For PE
Surgical Population
Cancer (n6,124)
No Cancer (n16,954)
P Value
All Patients
192 (3.1) 20 (0.33) 5 (0.08)
120 (0.7) 15 (0.09) 4 (0.02)
0.0001 0.0001
Death () Fatal PE () Nonfatal PE ()
Receiving UFH or LMWH.
Adapted from Kakkar et al. Thromb Haemost.
200594867-71.
18
PE Occurs After Hospital Discharge
In-hospital PE (n80)
After-discharge PE (n24)
Days
0
4
8
12
16
20
24
28
32
36
Adapted from Huber et al. Arch Surg
1992127310-3.
19
ENOXACAN II Design
21 Days
7 Days

Enoxaparin (40mg sc od) n 165
Enoxaparin(40mg sc od)
Placebo n167
Major abdominal surgery
Bilateral venography
Pre-op dose
Adapted from Bergqvist et al., New Engl J Med
2002346975?80.
20
ENOXACAN II Results
RRR, 60P0.02
RRR, 60P0.01

• 332 patients undergoing surgery for abdominal or
  pelvic tumours received enoxaparin (40 mg daily)
  for 1 week followed by enoxaparin or placebo for
  another 21 days
• Venography was performed at 30-day and 3-month
  follow-up
• At each follow-up, prolonged TP was associated
  with a 60 risk reduction for DVT

20
13.8
15
12.0
Incidence of DVT ( patients)
10
5.5
4.8
5
0
Follow-up
Enoxaparin (n165)
Placebo (n167)
Adapted from Bergqvist et al., N Engl J Med
2002346975?80.
21
FAME Design
7 Days
21 Days

Dalteparin (5000 IU sc od)
Dalteparin(5000 IU sc od) TED
No further prophylaxis
Major abdominal surgery
Bilateral venography(assessor-blinded)
Pre-Op dose TED graduated compression stockings
Adapted from Rasmussen et al., J Thromb Haemost
2006 4 238490.
22
FAME Results

• The ITT population consisted of 178 patients in
  the short-term prophylaxis group and 165 in the
  prolonged prophylaxis group
• Venography was performed on day 28
• Prolonged TP was associated with a 55 risk
  reduction for VTE and 77 risk reduction for
  proximal DVT

RRR, 55 P0.012
RRR, 77P0.009
16.3
20
15
8.0
Incidence ( patients)
7.3
10
5
1.8
0
Dalteparin
4 weeks
1 week
Adapted from Rasmussen et al., J Thromb Haemost
2006 4 238490.
23
Extended Thromboprophylaxis Meta Analysis

• 4 studies 2 double-blind and 2 open
• 1,037 patients
• Bilateral venography

710 days 45 weeks p DVT
15 6.5 lt
0.0005 Proximal DVT 5 1
lt 0.01 Symptomatic DVT 1 0.3
0.27
Adapted from Rasmussen et al. J Thromb Haemost
2005 3 Suppl 1P2213.
24
ESMO Clinical Recommendations
Should Patients With Cancer Undergoing Surgery
Receive Thromboprophylaxis?

1. Prophylaxis with LMWH (3400 - 5000 U once daily)
   or UFH (5000 U three times daily) is recommended.
   I, A.
2. Cancer patients undergoing elective major
   abdominal or pelvic surgery should receive
   post-discharge prophylaxis with LMWH for up to 1
   month after surgery I, A.

Levels of evidence IV and grades of
recommendation AD as used by the American
Society of Clinical Oncology.
25
ASCO VTE Guideline
Should Patients With Cancer Undergoing Surgery
Receive Thromboprophylaxis?

1. All patients undergoing major surgical
   intervention for cancer should be considered for
   thromboprophylaxis.
2. Patients undergoing laparotomy, laparoscopy,
   thoracotomy lasting greater than 30 minutes
   should receive pharmacological thromboprophylaxis
   with UFH or LMWH unless contraindicated.
3. Commenced preoperatively.

26
Should Patients With Cancer Undergoing Surgery
Receive Thromboprophylaxis?
ASCO VTE Guideline

1. Mechanical methods may be added to
   pharmacological methods but should not be used as
   monotherapy for VTE prevention unless
   pharmacological methods are contraindicated
   because of active bleeding
2. Combined pharmacological and mechanical
   prophylaxis may improve efficacy especially in
   the highest risk patients
3. Prophylaxis should be continued for at least 7 -
   10 days postoperatively. Prolonged prophylaxis
   for up to 4 weeks after major abdominal and
   pelvic surgery in patients with high risk
   features such as residual disease, obesity, and
   previous history of VTE

27
Conclusions

• VTE common after cancer surgery.
• Prophylaxis with LMWH effective and safe.
• Extended prophylaxis should be considered for
  highest risk populations.